Pubblicazioni

Autori:

Rossi, Barbara; Zenaro, Elena; Angiari, Stefano; Ottoboni, Linda; Bach, Simone Dorothea; Piccio, L; Pietronigro, Enrica Caterina; Scarpini, E; Fusco, M; Leon, A; Constantin, Gabriela

Titolo:

Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism

Anno:

2011

Tipologia prodotto:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Lingua:

Inglese

Formato:

Elettronico

Referee:

Sì

Nome rivista:

Journal of Neuroimmunology

ISSN Rivista:

0165-5728

N° Volume:

233

Numero o Fascicolo:

1-2

Intervallo pagine:

97-105

Parole chiave:

Cannabinoid CB1 receptor; Neuroinflammation; Lymphocyte trafficking; Integrins; Protein kinase A

Breve descrizione dei contenuti:

It is well known that the cannabinoid system has a significant role in the regulation of the immune responses. Cannabinoid receptors CB1 and CB2 are expressed on T lymphocytes and mediate the immunomodulatory effects of cannabinoids on T cell functions. Here we show that the treatment of proteolipid protein (PLP)139-151-specific T cells with SR141716A, a CB1 inverse agonist and prototype of the diarylpyrazoles series, induced a strong inhibition of firm adhesion in inflamed brain venules in intravital microscopy experiments. In contrast, SR144528, a potent CB2 inverse agonist, had no significant effect on both rolling and arrest of activated T cells. In addition, two analogs of SR141716A and CB1 inverse agonists, AM251 and AM281 inhibited encephalitogenic T cell adhesion suggesting that selective CB1 inverse agonism interfere with lymphocyte trafficking in the CNS. Flow cytometry experiments showed that CB1 inverse agonists have no effect on adhesion molecule expression suggesting that CB1 blockade interferes with signal transduction pathways controlling T cell adhesion in inflamed brain venules. In addition, integrin clustering was not altered after treatment with CB1 inverse agonists suggesting that adhesion blockade is not due to the modulation of integrin valency. Notably, the inhibitory effect exerted by AM251 and AM281 on the adhesive interactions was completely reverted in the presence of protein kinase A (PKA) inhibitor H89, suggesting that cAMP and PKA activation play a key role in the adhesion blockade mediated by CB1 inverse agonists. To further strengthen these results and unveil a previously unknown inhibitory role of cAMP on activated T cell adhesion in vivo in the context of CNS inflammation, we showed that intracellular increase of cAMP induced by treatment with Bt2cAMP, a permeable analog of cAMP, and phosphodiesterase (PDE) inhibitor theophylline efficiently blocked the arrest of encephalitogenic T cells in inflamed brain venules. Our data show that modulation of CB1 function has anti-inflammatory effects and suggests that inverse agonism of CB1 block signal transduction mechanisms controlling encephalitogenic T cells adhesion in inflamed brain venules by a PKA-dependent mechanism.

Id prodotto:

58675

Handle IRIS:

11562/347453

depositato il:

15 aprile 2011

ultima modifica:

2 giugno 2023

Citazione bibliografica:

Rossi, Barbara; Zenaro, Elena; Angiari, Stefano; Ottoboni, Linda; Bach, Simone Dorothea; Piccio, L; Pietronigro, Enrica Caterina; Scarpini, E; Fusco, M; Leon, A; Constantin, Gabriela, Inverse agonism of cannabinoid CB1 receptor blocks the adhesion of encephalitogenic T cells in inflamed brain venules by a protein kinase A-dependent mechanism «Journal of Neuroimmunology» , vol. 233 , n. 1-2 , 2011 , pp. 97-105

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